The variability could have significant clinical consequences for patients who switch from the branded product or from one generic version to another, said Gregory Krauss, M.D., of Johns Hopkins University, at the American Academy of Neurology meeting.

Dr. Krauss and two colleagues based their findings on pharmacokinetic data for five FDA-approved generic versions of carbamazepine that they obtained through the Freedom of Information Act.

The data included maximal blood concentrations of the drug (Cmax) and the area under the curve (AUC) for the five generics and the branded product. For each agent, the data covered a total of four studies, two each at doses of 200 and 400 mg.

The researchers found that three of the generics were close copies of the original drug in their pharmacokinetics, Dr. Krauss said.

For two generics, though, the mean values for Cmax and/or AUC were near the maximum difference from those for Tegretol allowed by the FDA. However, they were still technically legal.

The agency's rule is that the 90% confidence limits for AUC and Cmax measurements for a generic product must be in the range of 80% to 125% of values for the branded "index" drug.

Across studies, values for mean AUC varied by 6% to 7%; Cmax values varied from one another by 12% to 20%, Dr. Krauss reported.

The researchers also reanalyzed the data to determine potential changes in AUC and Cmax values for patients who switch from one generic product to another.

They found that switches between two pairs of generic formulations tested at the same doses could lead to changes in AUC of up to 21%. The 90% confidence limit in these comparisons was as low as 88% and as high as 127%.

Even bigger changes in maximal drug concentrations -- up to 40% -- could occur when switching between generic formulations, according to the data. The 90% confidence limits for Cmax in such switches ranged from 77% to 48%.

Such changes could lead to loss of efficacy and breakthrough seizures, Dr. Krauss said.

Dr. Krauss said the relative insolubility of carbamazepine was the reason for the variation. Solubility acts as a buffer for variations in absorption, so blood levels of insoluble agents are very sensitive to such variations.

"It's like putting a hose on hard dirt," he said.

For patients who would benefit from carbamazepine, he said, he prefers an extended-release version, which he characterized as providing "a steady drip" that keeps blood levels in a narrower range.

Jacqueline French, M.D., a neurologist at New York University, said the findings were new and important.

She agreed that switching from one carbamazepine version to another could lead to breakthrough seizures. It's often unclear why a patient with good epilepsy control suddenly has a seizure, she said.

"I take my hat off to Greg Krauss for getting the data," she said.

Dr. French noted that the results suggest that switching patients from branded carbamazepine to a generic form could be a false economy if it means patients need to have blood levels checked more frequently.

For patients with good seizure control on Tegretol whose insurance may demand use of generics, "it's a tough situation," she said.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.